1, 12-dimethyl-6-hydroxy-7-aroyl-1, 2, 3, 4, 9, 10, 11, 12-octahydrophenanthrene-1-car-boxylic acids, ethers and esters thereof



United States PatentO A 2,947,778 1,12-Dl1VIETHYL-6-HYDROXY 7 AROYL 1,2,3,4,9,

10,11,12 OCTAHYDROPHENANTHRENE-l-CAR- BOXYLIC ACIDS, ETHERS AND ESTERS THEREOF Roy H. Bible, In, Morton Grove, 111., assignor to G. D. Searle & Co., Chicago, 111., a corporation of Delaware No Drawing. Filed Sept. 23, 1953, Ser. No. 762,683

Claims. or 260-4685) The present invention relates to "polyhyd'rophenanthrene compounds, and is specifically concerned with 1,12 dimethyl 6 hydroxv- 7 aroyl l,2',3,4,9,10,11, 12-octahydrophenanthrene-1-carboxylic acids, ethers and esters thereof. The compounds of the present inventio can be represented by the structural formula Y l V 7 CH: I I

' an aromatic radical containing fewer than 9 carbon atoms. It can represent an aromatic hydrocarbon radical such as phenyl, methylphenyl, dimethylphenyl or ethylphenyl. It can 'also representyan aromatic halohydrocarbon radical such 'as chlorophenyl, bromophenyl, iodophenyl, dichlorophenyl, fribromophenyl, and similarly halogenated methylphenyl, dimethylphenyl, 'an'cl ethylphenyl radicals. In "addition, it can represent an alkoxyhydroc'ar'bon radical such as methoxyphenyl, dimethoxyphenyl, e'thoxyphenyl, and methoxymethylphenyl, a, common featureoft'he foregoing aromatic radicals being that they contain fewer thail carbon atoms;

- The compounds of the present invention can be manufactured from. such readily available resin acid 'deriva tives as methyl O-methylpodocarpate and eth'yl O-ethylpodocarpate. Illustrative of'a general method ofoperation, an alkyl O-alkylpoclocarpate of the structural E. coli.

Upon treatment of the resulting alkyl ester of 1,12- dimethyl a 6 al-koxy 7 aroyl 1,2,3,4,9,10,11,12 octahydrophenanthrene-l-carboxylic acid with pyridine hyd'rochloride as set, forthin detail hereinafter, there occurs cleavage, of the ether and ester groups with the formation of a1,12-dimethyl-6-hydroxy-7-aroyl-1,2,3,4,9,10,1 1, 1Z-octahydrophenanthrene-l-carboxylic acid. Selective hydrolysis ofthe G-alkoxy or the l-alkoxycarbonyl group canalso be achieved. By treatment of a chlorobenzene solution with aluminum chloride the ether function is preferentially hydrolyzed, whereas refluxing with morpholine followed by dilution with water causes preferential hydrolysis of the ester function.

The compounds of the present invention have valuable pharmacological properties. They are. anti-inflammatory agents and they are efiective in the treatment of inflammationof the iris. They have a phenylbutazone-like efiect on local edema, particularly foot edema. They have an estrogen-like effect on the cholesterol/phospholipid ratio in the serum. They also have anti-bacterial properties, exhibited, for example, against B. subtilis and Also they "are effective as selective shields of ultraviolet radiation.

This invention will appear more fully from the examples which follow. These examples are set forth by way of illustration only, and it will be understood that the invention is not to be construed as limited in spirit 7 Example I To a stirred mixture of 83 parts of methyl O-methylpodocarpate and 450parts of chlorobenzene, maintained at about 10-15 C., there is added a total of 75 parts of e aluminum chloride in several portions over a 10 minute period.' There is then added over a 30 minute period a solution of 42 parts of benzoyl chloride in 40 partsof chlorobenzene. The mixture is allowed to warm to room temperature gradually and is then allowed to stand 3 at about 25 C. for 18 hours, after which it is poured into several times its volume of ice water which has been acidifiednwith hydrochloric acid; The resulting mixture is distilled under reduced pressure until almost all of the chlorobenzene is removed, after which it isextracted with several portions of ether. W The combined ether extract is washed with 10% hydrochloric acid, with water, with 10% sodium hydroxide solutiongand finally with several portions of water, after which it is concentrated todryness; By several crystallizations of the non-volatile residue from aqueous acetic acid and then from aqueis subjected to an aluminum chloride-catalyzed conden ous methanol there is obtained the methyl ester of 1,12

dimethyl -6 methoxy 7 benzoyl 1,2,3-,4,9,10,11,12- octahydrophenanthrene-l-carboxylic acid which melts at about 114-119 C. and has the structural formula Example 2 v To a stirred mixture of 30 parts of methyl O-methylpodocarpate in 110 parts of chlorobenzene maintained at about l5 C. there is added 27 partsof aluminum chloride over a 10 minute period followed by a solution of 35 parts of p-chlorobenzoyl chloride in parts of chlorobenzene over a 30 minute period. The mixture is allowed to warm gradually to room temperature and then to stand for about'18 hours, after which it is poured into several times its volume of acidified ice water. Most of the chlorobenzene is removed by distillation under reduced pressure, andthe remaining mixture is extracted with several portions of ether. The combined ethereal extract is washedwith 10% hydrochloric acid, with water, with 10% sodium hydroxide solution, and with s'ever'alfiortions of water, and is then concentrated to dryness. By two crystalli'z ation's of the non-volatile residue from mixtures of ethyl acetate and petroleum' ether there is obtained the methyl ester of 1,12dirnethyl 6-rnethoxy-7- (p chlorobenzoyl)-1,2,3,4,9,10,11,12 octahydrophenanthrene-l carboxylic acid which melts at about 140-144 C. and has the structural formula CH3 OCHaH .W,

mo eooem Br on. P I

ac cooonl The specific rotation of a 1% ethanolicsolution'is 76. Infrared absorption maxima are observed at 5.80 and 6.03 microns.

, Example 4 To a stirred mixture of 30 parts of'rnethyl O methyl p'odocar'pate and 110 parts of chlo'r'obenz ene maintained at 10-15 C. there is added 27 partspf aluminum chloride over a 10 minute period followed by a solution of 34 parts of o-methoxybenzoyl chloride and 15 parts of chlorobenzene over a 30 minute period. Stirring is continued for 3 hours while the'mixtureis gradually allowed to warm to room temperature. It isthen maihtained at about C. for 18 hours, after which it is poured into several times its volume ofacidified ice water. Almost all of the chloroben'z'ene is removed by distillation under reduced pressure, and the remaining mixture is extracted with several portions of ether. The ethereal extract is washed successively With 10% hydrochloric acid, with water, with 10% sodium hydroxide solution, and with several portions of Water, after which it is concentrated to dryness. The residue is crystallized from aqueous methanol to afford the methylester of 1,,12-dimethyl-6- methoxy 7 (o methoxybenzoyl)-1,2,3,4,9,10,11,12.-

' 3 cients of about 24,000 and 3,400 respectively.

4 octahydrophenanthrene-l-carboxylic acid melting at about 118-121 C. The structural formula is o cm [a] =98. Infrared maxima are observed at 5.81 and 5.98 microns.

V E xiz mple 6 By the procedure of Example 1, with the substitution of 50 parts of o-ethylbenzoyl chloride for the benzoyl chloride, there is obtained thjmethyl ester of 1,12-dimethyl 6-methoxy-7-(o-ethylbenzoyl)-1,2,3,4,9,10,11,12- octahydrophenanthrene-l-carboxylic acid.

The specific rotation of a 1% .ethanolic solution is 102. Infrared maxima are seen at 5.83 and 6.07 microns. -The ultraviolet spectrumshows maxini'a at .250

and 32.0 .rnillimicrons with molecular extinction coeffi- Qie thyl sulfate, (46,2 are) is added, with staring, ll.

solution of 27.4 parts of podo carpic ,acid and12. 8, parts of sodiumhydroxidein 50% aqueousrethanol, .andthe resulting mixture is. boiled for 5 minutes-.andlallowed to cool. Theprecipitatede'thyl O-ethylpodocarpate is.c0l-

lectedpn a filter and washed withdilute sodium, carbonate solution 1 and. withwater. The ethyl Ofethylpodocarpate is dried thoroughly in a vacuum desiccator. A solution prepared frorn 19.7 parts of thislproduct' and 17.5. parts of benzoylchloride in 250 parts of .nitrobenzene. isIcooIed to O'iQl and treated with 1.6.2 parts ofaluminum chloride addedinqseveral portionsovena period of 1. hour. The mixture is stirredat 0 .C. for an additional.3 .hours, andthen allowed to stand at 0-5" C. for 100 hours and finally atabout 203. C. for 5 hours. .Jlhe. mixture is then i stirred with ice ,andrdilu'te hydrochloric acid. ..The nitrobenzene phase. .isrseparated, washed .with several portions of water, and distilled. with steam until the organic solvent is removed. vThe remaining 1 aqueous suspension is extracted with. ethyl .acetate, and the ethyl acetate solution 3 is Washed with water and concentrated to dryness under reduced pressure. The non-volatile residue consists substantially of the,et;hyl ester...of l,l2-dimethyl-6-ethoxy-7- benzoyl 1,2,3,4;9,10 ,11,12 octahydrophenanthrene-lcarboxylic acid which shows ultraviolet absorption max- 1 ima at 250 millimicrons with a molecular extinction coefficient of about 24,000 and at 320, millimicrons with a molecular extinction coefficient of about 3,400. The specific rotation of a 1% ethanolic solution is 103.

Example 8 A solution of 2parts ofthe methyl ster of 1,12-dimethyl 3 6,; 1116fl10XY q '7 benzoyl. v 1,2,3,4,9 ,10,1l,12.-

methanol yields 1,12 dimethyl 6 hydroxy 7 benzoyll,2,3,4,9,l0,11,12 octahydrophenanthrene 1 carboxylic acid which shows infrared maxima at 5.93 and 6.15 microns. This compound exhibits ultraviolet absorption maxima at 255 (shoulder), 277 and 350 millimicrons.

Example 9 A mixture of 12.2 parts of the methyl ester of 1,12- dimethyl 6 methoxy 7 benzoyl 1,2,3,4,9,10,11,12-

octahydrophenanthrene l carboxylic acid, 2.82 parts is dissolved in a large amount of water. The solution of the sodium salt of 1,12 dimethyl 6 methoxy 7 benzoyl 1,2,3,4,9,10,11,12 octahydrophenanthrene 1 carboxylic acid is filtered. On acidification of the filtrate the free acid is obtained which, on two recrystallizations from aqueous methanol, is obtained in crystals melting at about 213-216 0.

Example To a stirred mixture of 8 parts of aluminum chloride in 110 parts of chlorobenzene there is added a solution of 10 parts of the methyl ester of 1,12 dimethyl 6- methoxy 7 benzoyl 1,2,3,4,9,10,11,12 octahydrophenanthrene 1 carboxylic acid in 55 parts of chlorobenzene. Stirring is continued and the mixture is maintained at about 80 C. for an additional hour, after which it is cooled and poured into ice water. Dilute hydrochloric acid and benzene washings of the reaction vessel are added, and the organic solvents are removed by distillation under reduced pressure. The product remaining is then separated and washed by decantation with several portions of water. Purification by recrystallization from aqueous acetic acid yields the methyl ester of 1,12 dimethyl 6 hydroxy 7- benzoyl 1,2,3,4,9,10,11,12- octahydrophenanthrene 1 canboxylic acid melting at about 207-211 C.

What is claimed is:.

1. A compound of the structural formula CHI H3O 000R wherein R and R are members of the group consisting of hydrogen and lower alkyl radicals; and wherein AI is a monocyclic aromatic hydrocarbon radical containing fewer than 9 carbon atoms, monocyclic aromatic halohydrocarbon radical containing fewer than 9 carbon atoms, and monocyclic aromatic alkoxyhydrocarbon radical containing fewer than 9 carbon atoms.

The extract is then washed with water 2. A compound of the structural formula C Ha ([)(lower) alkyl HaO COO-(lower) alkyl wherein Y is a monocyclic aromatic hydrocarbon radical containing fewer than 9 carbon atoms.

3. Methyl ester of 1,12 dimethyl 6 methoxy 7- benzoyl 1,2,3,4,9,l0,11,12 octahydrophenanthrene 1- carboxylic acid.

4. A compound of the structural formula OH O-(lower) alkyl OO-Y C 0-haloary1 O0-a1koxyaryl Hi0 COO-(loweflalkyl wherein the alkoxyaryl radical is a monocyclic aromatic alkoxyhydrocarbon radical containing fewer than 9 carbon atoms.

7. Methyl ester of 1,12 dimethyl 6 methoxy 7 -(omethoxybenzoyl) 1,2,3,4,9,10,11,12 octahydrophenanthrene 1 carboxylic acid.

8. Lower alkyl ester of 1,12' dimethyl 6 hydroxy- 7 benzoyl 1,2,3,4,9,10,11,12. octahydrophenanthrene- 1 carboxylic acid.

9. 1,12 dimethyl 6 methoxy 7 benzoyl 1,2,3,4,- 9,10,11,12 octahydrophenanthrene 1 carboxylic acid.

10. 1,12 dimethyl 6 hydroxy 7 benzoyl 1,2,3,4,- 9,10,11,12 octahydrophenanthrene 1 carboxylic acid.

References Cited in the file of this patent UNITED STATES PATENTS 2,750,373 Bible June 12, 1956 2,767,162 Picha Oct. 16, 1956 2,851,485 Bible Sept. 9, 1958 2,854,474 Bible Sept. 30, 1958 

1. A COMPOUND OF THE STRUCTURAL FORMULA 